Telomerase contributes to tumorigenesis by a telomere length-independent mechanism

Stewart, Sheila A.; Hahn, William C.; O’Connor, Benjamin F.; Banner, Elisa N.; Lundberg, Ante S.; Modha, Poonam; Mizuno, Hana; Brooks, Mary W.; Fleming, Mark D.; Zimonjic, Drazen B.; Popescu, Nicholas C.; Weinberg, Robert A.

doi:10.1073/pnas.182407599

Cited by 401 publications

(347 citation statements)

References 49 publications

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“…The prevalence of reactivating telomerase for telomere length maintenance versus homologous recombinationbased telomere maintenance in human tumors suggests that telomerase functions go beyond telomere repair in promoting tumor growth (Blasco, 2002;Chang and DePinho, 2002;Stewart et al, 2002). Forced telomerase expression in ALT models confers growth advantages under all tested conditions, including limited cellular cross-talk, low seeding number and in anchorageindependent growth assays.…”

Section: Discussionmentioning

confidence: 99%

“…Although SV40LT inhibitory activity on the p53 and Rb tumor suppressor pathways are adequately replaced by similar p53 and Rb inhibitory activities, with the expression of human papillomavirus E6 and E7 oncoproteins (Kiyono et al, 1998), telomere maintenance by the ALT mechanism is unable to replace TERT expression and promote robust tumorigenesis in nude mice. This implies that the role of telomerase activity in cancer development goes beyond telomere maintenance (Stewart et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

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Telomerase promotes efficient cell cycle kinetics and confers growth advantage to telomerase-negative transformed human cells

Fleisig

Wong

2011

Oncogene

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Constitutive telomerase activity maintains telomere length and confers immortal phenotypes to human cancers. The prevalence of telomerase, rather than a homologous recombination-based mechanism, in telomere length maintenance suggests that telomerase also has auxiliary roles in tumorigenesis. Here, we investigate growth advantages provided by the telomerase enzyme in oncogene-transformed human cells that do not require telomerase activity for telomere length control. Our data suggest that in oncogene-transformed cells, telomerase activity accelerates cell growth kinetics in a cell cycle phase-specific manner and promotes anchorage-independent growth. Coculture experiments demonstrated that this growth advantage conferred by telomerase activity is not due to increased cellular cross-talk. Growth advantages provided by telomerase required all functional aspects of the enzyme. Dissociation-of-activity-in-telomerase mutants and other functionally defective versions of telomerase were unable to promote oncogene-transformed cell growth, suggesting that canonical telomerase activities may be involved. We conclude that telomerase provides advantages to oncogene-transformed human cells, thereby supporting the development of telomerasebased anticancer chemotherapies targeting these growthpromoting effects.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Telomerase promotes efficient cell cycle kinetics and confers growth advantage to telomerase-negative transformed human cells

Fleisig

Wong

2011

Oncogene

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“…To determine whether it was the telomere extension activity of telomerase that compensated for FEN1 depletion at the telomeres as suggested by our earlier work, we utilized a catalytically inactive, dominant-negative allele of hTERT (DNhTERT) (Figure 3a). This allele was chosen because earlier work showed that it had no impact on telomere stability in GM847 cells (Stewart et al, 2002). In contrast to that observed in GM847-hTERT cells, FEN1 depletion in GM847-DN-hTERT cells resulted in increased telomeric fusions (Figures 3b and c).…”

Section: Role Of Fen1 In Alt Tumor Cells a Saharia And Sa Stewartmentioning

confidence: 97%

“…A minimum of 100 cells were counted for each condition and the average for two experiments is presented. Cell culture, western blot analysis, viral constructs and production as well as metaphase preparation and statistical analyses were as described earlier (Stewart et al, 2002(Stewart et al, , 2003Saharia et al, 2008).…”

Section: Flap Endonuclease 1 Depletion In Telomerase-positive Cells Dmentioning

confidence: 99%

FEN1 contributes to telomere stability in ALT-positive tumor cells

Saharia

Stewart

2009

Oncogene

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Abrogation of telomere stability through loss-of-function mutations in telomere binding proteins contributes to genomic instability and cancer progression. Recently, Flap endonuclease 1 (FEN1) was shown to contribute to telomere stability in human cells that had not yet activated a telomere maintenance mechanism, suggesting that abrogation of FEN1 function influences the transformation process by compromising telomere stability and driving genomic instability. Here, we analyse the telomeres in human cancer cells following FEN1 depletion. We show that FEN1 is required for telomere stability in cells that rely on the alternative lengthening of telomere (ALT) mechanism. Indeed, FEN1 depletion resulted in telomere dysfunction, characterized by formation of telomere dysfunction-induced foci (TIFs) and end-to-end fusions in ALT-positive cells. In contrast, no telomere phenotype was observed in telomerase-positive cells on FEN1 depletion, suggesting that ongoing telomerase activity protected telomeres. In consonance with this, we found that expression of the catalytic component of telomerase (hTERT) but not an inactive allele rescued telomere dysfunction on FEN1 depletion in ALT cells. Our data suggest that mutations that arise in FEN1 affect telomere stability and genome fidelity by promoting telomere fusions and anaphase-bridge-breakage cycles, which further drive genome instability and thereby contribute to the transformation process.

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“…Telomerase is able to elongate telomeres (Greider & Blackburn, 1985); however, it often has diminished activity in adults, particularly in long‐lived species (Dong, Masutomi, & Hahn, 2005; Haussmann et al., 2007; Hornsby, 2007; Stewart et al., 2002; Tollefsbol & Andrews, 2001). There is some evidence that telomerase may be more active in bone marrow, gonads, and intestine cell lines in adult birds of long‐lived species ( Sterna hirundo; Oceanodroma leucorhoa ) compared to short‐lived ones ( Taeniopygia guttata; Tachycineta bicolor ) (Haussmann et al., 2007).…”

Section: Introductionmentioning

confidence: 99%

Magellanic penguin telomeres do not shorten with age with increased reproductive effort, investment, and basal corticosterone

Cerchiara

Risques

Prunkard

et al. 2017

Ecology and Evolution

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All species should invest in systems that enhance longevity; however, a fundamental adult life‐history trade‐off exists between the metabolic resources allocated to maintenance and those allocated to reproduction. Long‐lived species will invest more in reproduction than in somatic maintenance as they age. We investigated this trade‐off by analyzing correlations among telomere length, reproductive effort and output, and basal corticosterone in Magellanic penguins (Spheniscus magellanicus). Telomeres shorten with age in most species studied to date, and may affect adult survival. High basal corticosterone is indicative of stressful conditions. Corticosterone, and stress, has been linked to telomere shortening in other species. Magellanic penguins are a particularly good model organism for this question as they are an unusually long‐lived species, exceeding their mass‐adjusted predicted lifespan by 26%. Contrary to our hypothesis, we found adults aged 5 years to over 24 years of age had similar telomere lengths. Telomeres of adults did not shorten over a 3‐year period, regardless of the age of the individual. Neither telomere length, nor the rate at which the telomeres changed over these 3 years, correlated with breeding frequency or investment. Older females also produced larger volume clutches until approximately 15 years old and larger eggs produced heavier fledglings. Furthermore, reproductive success (chicks fledged/eggs laid) is maintained as females aged. Basal corticosterone, however, was not correlated with telomere length in adults and suggests that low basal corticosterone may play a role in the telomere maintenance we observed. Basal corticosterone also declined during the breeding season and was positively correlated with the age of adult penguins. This higher basal corticosterone in older individuals, and consistent reproductive success, supports the prediction that Magellanic penguins invest more in reproduction as they age. Our results demonstrate that telomere maintenance may be a component of longevity even with increased reproductive effort, investment, and basal corticosterone.

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Telomerase contributes to tumorigenesis by a telomere length-independent mechanism

Cited by 401 publications

References 49 publications

Telomerase promotes efficient cell cycle kinetics and confers growth advantage to telomerase-negative transformed human cells

Telomerase promotes efficient cell cycle kinetics and confers growth advantage to telomerase-negative transformed human cells

FEN1 contributes to telomere stability in ALT-positive tumor cells

Magellanic penguin telomeres do not shorten with age with increased reproductive effort, investment, and basal corticosterone

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